The objective of this project is to develop intraoral controlled- release therapeutic systems for antibiotics/antimicrobial and antifungal agents for the treatment of periodontal disease, AIDS- related oral diseases and other opportunistic oral mycotic infections. Biocompatible copolymers of hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) have been used to produce a membrane-controlled delivery system for tetracycline that should be suitable for short-term intraoral treatment of periodontal disease. Results with this system have shown that the hydrogel copolymers used in the Intraoral Fluoride Releasing Device also can be used for the delivery of large organic molecules in vivo. In a study in primates, ten days of treatment with tetracycline controlled-release pellets releasing 0.4 to 1.0 mg of tetracycline per day produced significant decreases in crevicular fluid flow, number of bleeding sites on probing, and bacterial morphotypes in subgingival plaque samples associated with periodontal disease. Prototype controlled-release pellets for chlorhexidine have been fabricated using the same biocompatible copolymers used with the tetracycline and fluoride systems. These pellets released biologically active chlorhexidine for at least two weeks. The behavior of these pellets in the presence of saliva is being evaluated. It should be possible to use this technology to develop intraoral controlled-release delivery systems for the lower molecular weight antifungal agents. Such systems could be beneficial in immunocompromised individuals.